Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation
Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation
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DOI：
10.1016/j.pain.2011.02.051
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发表时间：
2011-07-01
期刊：
影响因子：
7.4
通讯作者：
Geppetti, Pierangelo
中科院分区：
文献类型：
--
作者：
Nassini, Romina;Gees, Maarten;Geppetti, Pierangelo
铂类抗癌药物会引起神经毒性。特别是，奥沙利铂会产生早期发展、疼痛和冷加重的感觉异常。然而，这些麻烦和剂量限制性不良反应的机制尚不清楚。我们假设瞬时受体电位锚蛋白1（TRPA 1），一种由氧化应激和低温激活的阳离子通道，有助于奥沙利铂和顺铂引起的机械和冷超敏反应。在离体豚鼠肺动脉中，奥沙利铂和顺铂通过TRPA 1刺激和降钙素基因相关肽从感觉神经末梢释放介导引起谷胱甘肽敏感性舒张。在培养的小鼠背根神经节神经元或暴露于奥沙利铂或顺铂的幼稚中国仓鼠卵巢（CHO）细胞中未观察到钙反应。然而，奥沙利铂和较低效力的顺铂在表达小鼠TRPA 1的CHO细胞中诱发谷胱甘肽敏感性钙反应。奥沙利铂单次给药可在大鼠中产生机械性和冷痛觉过敏，TRPA 1拮抗剂HC-030031可选择性减轻该效应。奥沙利铂给药引起小鼠机械性和冷异常性疼痛。这两种反应在TRPA 1缺陷小鼠中均不存在。顺铂引起的机械性异常性疼痛，这种作用在TRPA 1缺陷小鼠中减少。因此，TRPA 1是奥沙利铂诱发的机械和冷超敏反应所必需的，并有助于顺铂诱发的机械异常性疼痛。通道激活最有可能是由谷胱甘肽敏感分子引起的，包括活性氧及其副产物，这些分子是在组织暴露于来自伤害性神经末梢周围细胞的铂类药物后产生的。(C)2011年国际疼痛研究协会。Elsevier B. V.出版，保留所有权利。
Platinum-based anticancer drugs cause neurotoxicity. In particular, oxaliplatin produces early-developing, painful, and cold-exacerbated paresthesias. However, the mechanism underlying these bothersome and dose-limiting adverse effects is unknown. We hypothesized that the transient receptor potential ankyrin 1 (TRPA1), a cation channel activated by oxidative stress and cold temperature, contributes to mechanical and cold hypersensitivity caused by oxaliplatin and cisplatin. Oxaliplatin and cisplatin evoked glutathione-sensitive relaxation, mediated by TRPA1 stimulation and the release of calcitonin gene-related peptide from sensory nerve terminals in isolated guinea pig pulmonary arteries. No calcium response was observed in cultured mouse dorsal root ganglion neurons or in naive Chinese hamster ovary (CHO) cells exposed to oxaliplatin or cisplatin. However, oxaliplatin, and with lower potency, cisplatin, evoked a glutathione-sensitive calcium response in CHO cells expressing mouse TRPA1. One single administration of oxaliplatin produced mechanical and cold hyperalgesia in rats, an effect selectively abated by the TRPA1 antagonist HC-030031. Oxaliplatin administration caused mechanical and cold allodynia in mice. Both responses were absent in TRPA1-deficient mice. Administration of cisplatin evoked mechanical allodynia, an effect that was reduced in TRPA1-deficient mice. TRPA1 is therefore required for oxaliplatin-evoked mechanical and cold hypersensitivity, and contributes to cisplatin-evoked mechanical allodynia. Channel activation is most likely caused by glutathione-sensitive molecules, including reactive oxygen species and their byproducts, which are generated after tissue exposure to platinum-based drugs from cells surrounding nociceptive nerve terminals. (C) 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.